PT2083811T - Methods of treating down's syndrome, fragile x syndrome and autism - Google Patents

Description

DESCRIPTION

METHODS OF TREATMENT OF DOWN SYNDROME, X SYNDROME

FRAGILE AND AUTISM

BACKGROUND OF THE INVENTION Down syndrome, fragile X syndrome and autism are genetic and developmental disorders that affect daily functioning, including learning, memory, speech, social skills and behavior. Currently available treatment regimens for humans with mental retardation, Down syndrome, fragile X syndrome and to aid in daily functioning include, for example, behavioral modifications and treatment with a wide range of drugs including antidepressant and antipsychotic drugs. However, these regimens are often ineffective or may produce undesired side effects with their long-term use, particularly in the case of the use of antipsychotic drugs. There is thus a need to develop new, improved and effective methods for the treatment of mental retardation, Down syndrome, fragile X syndrome and autism. WO 2005/025559 describes the treatment of gastroparesis and non-ulcer dyspepsia with GABA B agonists. WO 2007/053596 (prior art under art.54 (3) EPC) relates to modulation of mediated neurogenesis by the GABA receptor.

SUMMARY OF THE INVENTION The present invention provides compositions for use in the treatment of humans having Down's syndrome, fragile X syndrome and autism.

We also describe a method of treating a human having at least one condition selected from the group consisting of Down syndrome, fragile X syndrome and autism and autism spectrum disorders by administering a composition comprising a gamma- aminobutyric acid, particularly a composition comprising a composition of Formula I:

More particularly, the composition comprises baclofen, baclofen being administered to the human at a dose of about 2 mg per day for days 1, 2 and 3 of the treatment, a dose of about 4 mg per day for days 4, 5 and 6 of the treatment at a dose of about 6 mg per day during days 7, 8 and 9 of the treatment, a dose of about 10 mg per day during days 10, 11 and 12 of the treatment, a dose of about 20 mg per day during days 13, 14 and 15 of the treatment, a dose of about 30 mg per day during treatment days 16, 17 and 18 and a dose of between about 30 mg to about 80 mg per day during the duration of treatment; or baclofen is administered to the human at a dose of about 15 mg on days 1, 2 and 3 of the treatment, a dose of about 30 mg on days 4, 5 and 6 of the treatment, a dose of about 45 mg on days 7, 8 and 9 of the treatment, a dose of about 60 mg during days 10, 11 and 12 of the treatment and a dose of between about 60 to about 80 mg per day for the duration of the treatment.

Preferably, the composition includes a mole percent of R-baclofen, relative to the total R-baclofen and S-baclofen, of at least 51 percent in the composition.

Preferably, baclofen is administered to the human in a dosage regimen of at least one member selected from the group consisting of about 1 mg twice daily, about 2 mg twice daily, about 3 mg twice daily , about 5 mg twice daily, about 10 mg twice daily, and about 10 mg three times a day.

In certain embodiments of the present invention, the composition further comprises at least one M1 muscarinic receptor antagonist.

The advantages of the claimed invention may include, for example, the treatment of Down syndrome, fragile X syndrome, and autism in a manner that may ameliorate symptoms (eg, reduced anxiety and irritability; increased cognitive function, communication, and / or social interaction), effectiveness or reduce side effects, and thus improve tolerability for use over a relatively long period of time without significant side effects. The present invention may provide an effective treatment for a subject having mental retardation, Down Syndrome, fragile X syndrome and / or autism or autism spectrum disorders.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the effects of racemic baclofen on inhibition of burial behavior of berlinds in fragile (Fmr) knockout (KO) (n = 7-8 mice / group) mice. The data are expressed as the mean value ± SEM (standard error of the mean) of the number of buried berlinds. Figure 2 shows the effects of R (+) - baclofen on burial behavior of berlinds in Fmrl KO mice (n = 10-16 mice / group). The data are expressed as the mean value of buried marbles ± SEM. An asterisk (*) indicates that data for the 10 mg / kg dose were significantly lower (p <0.05) than all other groups. Figure 3 shows the effects of S (-) - baclofen on burial behavior of berminds of Fmrl KO mice (n = 11-15 mice / group). The data are expressed as the mean value of buried marbles ± SEM. The # symbol indicates that data for the dose of 1 mg / kg were significantly higher than for the dose of 0 mg / kg. The asterisk (*) indicates that the 50 mg / kg dose was significantly different (p <0.05) from all other groups. Figure 4 shows the effects of R (+) - baclofen and S (-) - baclofen on audiogenic seizures in Fmr KO mice (n = 9-10 mice / group). Data are expressed as the percentage of mice treated with vehicle (0 mg / kg), R (+) - or S (-) - baclofen, which exhibited audiogenic seizures. Figure 5 shows the effects of R (+) - and S (-) - baclofen on open field activity of male FmrI KO mice. The data are expressed as mean ± SEM of the total distance traveled. The # symbol indicates that the data for vehicle treated Fmrl KO mice are significantly higher than for wild-type (WT) mice. An asterisk (*) indicates that the vehicle treated FmR1 KO mice were significantly larger than the respective dose of R (+) - or S (-) - baclofen. Figure 6 shows the dicyclomine inhibition of berlind burial behavior in fragile X knockout (KO) mice (n = 3-5 mice / group). Data are expressed as the mean number of buried marbles ± SEM. Figure 7 shows audiogenic seizures in young FmrI KO mice with or without dicyclomine treatment (Dytc.). Data are presented as the percentage of mice treated with vehicle (0 mg / kg) or dicyclomine (40 mg / kg) which presented audiogenic seizures.

DETAILED DESCRIPTION OF THE INVENTION

The features and further details of the invention will now be described more particularly and pointed out in the claims. It will be appreciated that particular practical embodiments of the present invention are set forth by way of illustration and not as limitations of the invention. The main features of the invention may be employed in various practical embodiments of the present invention without departing from the scope of the invention.

In one embodiment of the present invention the invention provides a composition for use in a method of treating a human comprising a step of administering to a human having at least one condition selected from a group consisting of Down syndrome, fragile X and autism, a composition comprising a gamma-aminobutyric acid agonist (GABA), such as a GABA (B) receptor agonist (also referred to herein as "GABA (B) agonist" or "GABAB agonist"). GABA (gamma-aminobutyric acid) is an abundant neurotransmitter in the mammalian brain. GABA, like other neurotransmitters, including L-glutamate, serotonin and acetylcholine, activates ionotropic and metabotropic receptors. Ionotropic receptors are ligand-dependent ion channels which transfer rapid synaptic transmissions, whereas metabotropic G-coupled receptors modulate synaptic transmission through intracellular effector systems. GABA exerts its effect through ionotropic receptors dependent on ligands GABA (A) (also referred to as "GABAA"), GABA (C) (also referred to as "GABAC") and GABA (B) ) to produce slow and prolonged inhibitory synaptic signals through activation of Cl conductance, which may be allosterically modulated by psychoactive drugs, such as benzodiazepines, barbiturates and neurosteroids.

Subunits of the GABA receptor (A) have homology at the level of the sequence with the nAChR family of subunits. The family of GABA receptor subtypes (A) exists, these being generated by alternative processing of alpha 1-6, beta 1-4, gamma 1-4, delta, epsilon, pi, theta, and rhe 1-3 to form complexes proteins. Several GABA (A) subunits present distinct patterns of spatial and temporal expression that may have specific physiological roles at the tissue level. GABA (A) receptor proteins are characterized by the presence of a cleavable peptide signal, a large extracellular N-terminal, three transmembrane domains, one large cytoplasmic domain followed by another transmembrane domain and one C-terminal extracellular domain. The other common domain is referred to as the Cys-loop, there being two Cys-loops separated by thirteen amino acids in the extracellular domain of the receptor. The regions between the third and fourth transmembrane domains and the large cytoplasmic loop are less conserved among several GAA subunits, which may confer subunit-specific functionality. GAA genes are distributed in clusters along the human genome (chromosomes 4, 5, 15 and X, delta subunit on chromosome 1).

GABA (B) receptors are gamma-aminobutyric acid (GABA) metabotropic receptors that are bound to potassium channels by G proteins (Chen K, et al., Brain Res Buli 67: 310-8 (2005) ). GABA (B) receptors are found in the autonomic central and peripheral nervous system. GABA (B) receptors can stimulate potassium channels, which may result in hyperpolarization of the neuron, prevent the influx of sodium channels, and thus release the neurotransmitter. GABA (B) receptors may also reduce adenylyl cyclase activity and decrease calcium conductance in a neuron.

GABA (B) receptors are structurally similar to metabotropic glutamate receptors, and are divided into two subtypes, GABA (B) 1 and GABA (B) 2, which appear to form as heterodimers in neuronal membranes through binding by carboxyl termini.

An "agonist", as used herein, is a compound that activates cell signaling. For example, a GABA receptor agonist (B) activates GABA (B) receptor mediated cellular signaling and an Î ± 2 -adrenergic receptor mediated Î ± 2 -adrenergic agonist active.

The GABA agonists employed in the methods of the invention preferentially cross the blood brain barrier.

GABA agonists for use in the methods described herein may inhibit the release of glutamate into the central nervous system, such as in the cortex and basal ganglia of the central nervous system.

In another embodiment of the present invention, the composition includes a compound of formula I:

Formula I is baclofen, which is also referred to as β- (Aminomethyl) -4-chlorobenzenepropanoic acid; β- (Aminomethyl) -β-chlorohydrocinnamic acid; Y-amino-β- (p-chlorophenyl) butyric acid; β- (4-chlorophenyl) GABA. Baclofen is also referred to as Baclon, Lioresal, Kemstro and Myospan. The composition may include the use of a GABA receptor agonist (B) in combination with, for example, Formula II:

Formula II is 2-amino-6-trifluoromethoxybenzothiazole and is also referred to herein as "riluzole" (see, for example, U.S. Patent 4,370,338). Formula II is approved by the FDA (U.S. Food and Drug Administration) for the treatment of amyotrophic lateral sclerosis. It has multiple activities, including inhibition of presynaptic glutamate release through inactivation of P / Q type calcium channels, increased glutamate uptake in astrocytes, and inhibition of voltage-dependent sodium channels in central nervous system neurons of mammals. It has also been reported to potentiate AMPA / KA receptor mediated transmission, such as increasing brain-derived neurotrophic factor. It has been demonstrated that riluzole has neuroprotective activity, anticonvulsive activity, anxiolytic activity, and antidepressant activity in animal and human models. The subject may be treated with salts (eg, acid salts, basic salts, HCl, oxalate, calcium, sodium, magnesium, lithium), prodrugs, polymorphs and other structural and functional derivatives of the compounds such as Formulas I and II , described herein. Mental retardation means that a subject has less than average intelligence. Intelligence describes the subject's ability to think, learn, and solve problems. A subject with mental retardation may have difficulty learning, may take longer to learn social skills, such as how to communicate, and may be less able to take care of him or herself and live alone or as an adult. Down syndrome is a disorder that includes a combination of birth defects, including some degree of mental retardation, characteristic facial details and often cardiac defects, increased infections, problems with vision and hearing, and other health problems. The severity of these problems varies greatly between the affected subjects. Down Syndrome is usually caused by an additional copy of chromosome 21 and is also referred to as trisomy 21. Fragile X syndrome, as implicit in its name, is associated with a fragile site expressed as a isochromatic gap in the metaphase chromosome in the mapping position Xq 27.3. Fragile X syndrome is a genetic disorder caused by a mutation in the 5 'untranslated region of the fragile X mental retardation I gene (FMR1), located on the X chromosome. The mutation that causes the syndrome Fragile X is associated with a CGG repeat in the fragile X gene retarded FMR-1. When a subject possesses more than about 200 CGG repeats, the fragile X gene is found to be hypermethylated, silenced, Fragile X Mental Retardation (FMRP) protein is not produced and the subject is diagnosed while having the fragile X syndrome (See, for example, U.S. Patent Nos. 6,107,025 and 6,180,337). Fragile X syndrome segregates as a dominant X-linked disorder with reduced penetrance. Any of the sexes, when carrying the fragile X mutation, may exhibit mental deficiency, which is variable in terms of severity.

Children and adults with fragile X syndrome have varying degrees of mental retardation or learning disabilities and behavioral and emotional problems, including characteristics and trends similar to those of autism. Young children with fragile X syndrome often have delays in developmental milestones, such as learning to sit, walk and talk. Affected children may have frequent acts of anger, difficulties in paying attention, frequent seizures (eg, temporal lobe seizures), are often highly anxious, easily overloaded, may have sensory overexcitation disorders, gastrointestinal disorders, may have speech problems and unusual behaviors such as hitting and biting hands. Fragile X syndrome can be diagnosed by an established genetic test performed on a sample (e.g., blood sample, buccal sample) of the subject. The test determines whether a mutation, or a pre-mutation, is present in the FMR-1 gene of the subject.

Subjects with fragile X syndrome may also have autism, attention deficit disorders, and / or obsessive-compulsive disorder. Fragile X syndrome is a prevalent form of hereditary mental retardation and is characterized by developmental delays, attention deficit disorders, and autism-like behaviors (Jin, P., et al., Hum Mol Genet 9: 901-908 ( 2000)).

About 5% of all children diagnosed with autism have a mutation in the FMR1 gene and also have fragile X syndrome (FXS). About 15 to about 20% of subjects with fragile X syndrome meet the full diagnostic criteria for autism. Although mental retardation is a hallmark of fragile X syndrome, subjects with fragile X syndrome often exhibit autistic characteristics that range from shyness, poor eye contact, and social anxiety, to mild cases, to beating with the hands, biting of hands and persevering speech in severely affected subjects. Subjects with fragile X syndrome exhibit other symptoms associated with autism, such as attention deficit hyperactivity disorder, convulsions, hypersensitivity to sensory stimuli, obsessive-compulsive behavior, and altered gastrointestinal function. The FMR1 mutation prevents the expression of a single protein (FMRP). Brain development in the absence of FMRP gives rise to the main symptoms of fragile X syndrome. A key tool that allows a better understanding of the function of FMRP has been the development of Fmrl knockout mouse models.

In addition to the main symptoms, children with fragile X syndrome frequently exhibit severe behavioral disorders such as irritability, aggression and self-injurious behaviors. In a recent study of male subjects with fragile X syndrome (ages 8-24), 79% self-injurious behavior and 75% aggressive behavior of the subjects were observed during a two-month observation period (Hessl, D., et al., The National Fragile Foundation Quarterly, Issue 25: 10-13 (2006)). Despite the common occurrence of irritable, aggressive and self-injurious behavior in subjects with fragile X syndrome, little research has been done evaluating treatments for these symptoms.

Although there has been little research on subjects with fragile X syndrome, serious behavioral disturbances such as self-injurious behavior, aggression, and cholera ataxia often occur in individuals with autism (McCracken, JT, et al., N. Engl. J. Med. 347: 314-321 (2002)), and numerous clinical trials have been conducted evaluating a variety of therapeutic treatments. Behavioral therapy may provide benefits, but it is highly individualized and has not yet been evaluated in randomized clinical trials (Schreibman, L., J. Autism Dev. Discord 5: 373-378 (2002)). Likewise, multi-drug treatments of various chemical classes have met with limited success (McDougle, C.J., et al., Child Adolesc. Psychiatr Clin, N. Am. 9: 201-224 (2002)). Risperidone, an atypical antipsychotic, has been used to treat behaviors in subjects with autism (McCracken, J.T., et al., N. Engl. J. Med. 347: 314-321 (2002)). However, risperidone produces a number of undesirable side effects including increased appetite (73%) and weight gain (2.7 kg over 8 weeks), fatigue (59%), drowsiness (49%), drooling (27%) and dizziness (16%) (McCracken, JT, et al., N. Engl. J. Med. 347: 314-321 (2002)). There are also unresolved safety concerns that long-term therapy may cause extrapyramidal symptoms and that high levels of prolactin can affect sexual growth and maturation. These side effects limit the tolerability and utility of risperidone alone for the treatment of irritable aberrant behavior in subjects with autism. No formal studies have been published in subjects with fragile X syndrome, however clinical experience with atypical antipsychotics, such as risperidone alone, is consistent with the results observed in subjects with autism (McCracken, JT, et al., N. Engl. J. Med. 347: 314-321 (2002); Berry-Kravis, E., et al., Ment. Retard. Dis. Res. Rev. 10: 42-48 (2004)). Specifically, risperidone alone reduces the irritability behavior, but the side effect profile limits its use alone in subjects with fragile X syndrome.

Initial studies of the behavioral phenotype of Fmr KO mice on a mixed genetic background reported that Fmr KO mice exhibited increased exploratory and locomotor activity compared to wild-type controls, and also a slight learning disability in the Morris water maze, (Bakker, CE, et al., Cell 78: 23-33 (1994)). This learning disability has been analyzed in more detail by several groups using the Morris water task, the maze of water in the form of plus (shaped-water maze), the paradigms of operant conditioning, fear conditioned mice, passive avoidance, and the radial labyrinth (Bakker, CE, et al., Cell 78: 23-22 (1994)) Fmr KO mice have weakened learning processes when evaluated in assays that have not yet been attempted. Fmrl KO mice have indeed a weakened learning that is clearly task dependent. Learning and memory performance of Fmr KO mice is likely to be genetically dependent (Paradee, W., et al., Neuroscience 94: 185-192 (1999).) Although the learning and memory phenotypes of the Fmrl KO mice were challenging and somewhat elusive, there is sufficient data indicating that Fmrl KO mice are hyperactive, have altered responses in tests anxiety, and altered sensorimotor coupling (Mineur, Y.S., et al., Hippocampers 12: 39-46 (2002)). The FMRP protein can regulate behavioral states of activity / excitation, anxiety-related responses, and social interactions (Bakker, CE, et al., Cell 78: 23-33 (1994); Peier, AM, et al., Hum. Mol. Genet 9: 1145-1159 (2000)).

In challenging Fmrl KO mice with different test situations, KO mice have been shown to be hyperactive, may exhibit increased anxiety-like responses, demonstrate abnormal social interactions, and demonstrate poor learning and memory. Fmrl KO mice exhibit several abnormal behavioral responses that parallele the symptoms of FXS. The behavioral responses of Fmrl KO mice depend on their genetic background. FmR1 KO mice from particular genetic backgrounds exhibit an increase in autism-like traits. Specifically, Fmrl KO mice with a hybrid C57BL / 6J X DBA / 2 F1 (D2-Fmr1F) hybrid genetic background exhibit increased open field stereotypes, an increase in obsessive-type responses in the burying task, and have social interactions while FmRl KO mice with a hybrid C57BL / 6J X 129SI / SvImJF (129-FmRlF) gene appear to have poor social recognition. The fact that only a few FmR1 KO strains exhibit an increase in autism-like traits is consistent with observations that only 15-20% of FXS individuals have autism, and may have variations in FXS due to the genetic background. Other models of FXS mice may exhibit unique characteristics of the autism type. (Spencer, C.M., et al., Genes, Brain and Behavior, 4: 420-430 (2005)). Cognitive behavioral therapy has been used to improve language and socialization in fragile X syndrome and autism. In addition, many classes of psychiatric drugs are used in clinical practice to treat symptoms and behaviors in both populations (Berry-Kravis, E. et al., Ment. Retard. 2004), Malone, RP, et al., CNS Drugs 19: 923-924 (2005)). In recent years, pharmacological treatment with the atypical antipsychotic risperidone has been commonly employed to increase non-pharmacological approaches in the treatment of individuals with autism. A randomized, placebo-controlled trial of risperidone in autistic children demonstrated a significant improvement in the irritability subscale of the Aberrant Behavior Checklist and Clinicai Global Impressions-Improvement (McCracken, JT, et al., N. Engl. : 314-321 (2002)). However, adverse effects included weight gain, increased appetite, fatigue, drowsiness, dizziness, and drooling. Social isolation and communication have not been improved by the administration of risperidone and adverse effects, such as extrapyramidal symptoms and dyskinesias, have been associated with the use of risperidone in autistic children (Malone, RP, et al., J. Am. Child Adolescent Psychiatry 41: 140-147 (2002)).

Although a number of other drugs, including antipsychotics, antidepressants, and anticonvulsants, present mixed results in the treatment of various symptoms and behaviors associated with autism and fragile X syndrome; there is a need to develop new treatments.

As described herein, R-baclofen may be more potent than S-baclofen in reducing obsessive-compulsive and repetitive behavior, and for reducing audiogenic seizures, with minimal side effects. R-baclofen may be useful for the management of typical problem behaviors, such as irritability and aggression, in humans with fragile X syndrome. Baclofen can improve aberrant irritable behavior and may also have improved safety and tolerability profile compared to atypical antipsychotics in the treatment of fragile X syndrome and / or autism. Baclofen may be used in combination with other medicinal products, such as risperidone, antipsychotics, Group I mGluR antagonists and M1 muscarinic receptor antagonists. The pharmacokinetics of baclofen and M1 muscarinic antagonists, such as dicyclomine, in mice to define systemic exposure may be evaluated. The burial behavior of berlinds in rats is considered as a model of obsessive-compulsive disorder (OCD) in humans (Matushita, M., et al., Med. Bull. Fukuoka Univ. 32: 159- 165 (2005)). The data described herein demonstrate that baclofen inhibits the burial behavior of berlinds.

Subjects with autism may have several symptoms that can range from mild to severe. Such symptoms may include difficulties in interacting with others; friendship establishment; communication problems; both with spoken language and with non-verbal gestures; insistence on resemblance; and some degree of mental retardation or learning disabilities in most, but not all, affected children. Subjects with a mild autism spectrum disorder, referred to as Asperger's syndrome, may share some of the characteristics of autism, have normal intelligence, and can learn to speak at the expected age. Autism is usually diagnosed by observing the child's behavior and screening tests that evaluate a number of characteristics and behaviors associated with autism. Subjects with autism may also have, for example, obsessive-compulsive behaviors, sleep disorders and / or gastrointestinal disorders. A wide variety of psychiatric drugs are used to treat symptoms and improve the behavior of autism subjects. Antipsychotics are commonly used to treat behavioral problems associated with moderate to severe autism. Risperidone, an atypical antipsychotic that is used to treat aggression, hyperactivity, and other disorders associated with autistic behavior and aberrant behaviors in fragile X syndrome, may be used in combination with GABA agonists, M1 muscarinic receptor antagonists and Group I mGluR antagonists in the methods described herein. The antagonism of 5-HT2a and D2 receptors is considered crucial for the efficacy of atypical antipsychotics in schizophrenia, with the higher occupancy of the 5-HT2A receptor versus the D2 receptor being the key in decreasing the side effects of movement. Although all atypical antipsychotics share these two pharmacological actions, they differ because they have variable activity in other serotonin and dopamine receptors. Perospirone, an atypical antipsychotic drug approved in Japan for the treatment of schizophrenia, has pharmacological properties different from risperidone, and may be useful in the treatment of autism, mental retardation, and fragile X syndrome. The active metabolite of perospirone, hydroxysperospirone, has a pharmacological profile that may be useful in the treatment of anxiety and obsessive-compulsive behavior. For example, hydroxysperospirone achieves relatively high plasma concentrations that are acceptable for safety and tolerability levels in humans, and may contribute significantly to the efficacy observed during perospire treatment. The recent characterization of mutant mice, which model human genetic disease and exhibit autism-like traits, provides an opportunity to evaluate pharmacological interventions in autism-like and well-characterized genetically induced behaviors. Autism is a disorder characterized by deficiencies in social interaction and communication, such as restricted, repetitive and stereotyped patterns of behavior, interests and activities (DSM-IV). The etiology of autism can be medically diagnosed to less than 10% of individuals and for many of these the diagnosis is attributable to deficits of unique genes such as Fragile X syndrome, neurofibromatosis or tuberous sclerosis. There is considerable evidence that the remaining cases of "idiopathic" autism represent a largely inherited disorder. Twin studies and screening data from whole genomes suggest that interactions between at least 10 genes predispose the development of autism. Furthermore, it seems that environmental and epigenetic factors contribute to variable expression in genetically predisposed individuals. The complex interaction of genetic and non-genetic factors in the etiology of "idiopathic" autism has prevented the development of representative animal models and the development of new pharmaceutical treatments.

In contrast to the complexity of "idiopathic" autism, a number of human monogenic syndromes have a high incidence of autism. Animal models are available for a number of these monogenic human syndromes. These animal models of isolated gene defects are providing new ideas for potential pharmaceutical treatments for diseases such as neurofibromatosis and fragile X syndrome. Fragile X knockout mice (Fmrl), which model the defect in the gene isolated from the human fragile X syndrome, are used. Some of these mice, such as some humans with fragile X syndrome, have autistic behaviors.

The compositions of the invention may be employed in the further treatment of conditions which may be associated with autism or fragile X syndrome, for example, Coffin-Lowry syndrome, Cohen's syndrome, Duchenne / Becker muscular dystrophies, Neurofibromatosis, de Joubert syndrome, Lujan-Fryns syndrome, PTEN mutations, Noonan syndrome, Orstavik syndrome, ARX mutations, CHARGE, Angelman syndrome, Nance-Horan syndrome, Prader-Willi syndrome, brain dysgenesis syndrome and Smith's syndrome -Lemli-Optiz.

The compositions of the invention may be employed in the treatment of pervasive developmental disorders without any identified origin and autism and other disorders of brain development.

The compositions of the invention may also be employed in the treatment of disorders of the brain including Autism Spectrum Disorders (Pervasive Developmental Disorders), Rett syndrome, Childhood Disintegrative Disorder, , Asperger's Syndrome and Tuberous Sclerosis.

The compositions of the invention may be employed to treat deficits / symptoms, for example, learning deficits, memory, executive function, attention and / or processing speed. Such deficits may be deficits associated with or observed in subjects with mental retardation, fragile X syndrome, Down syndrome and autism; and pervasive developmental disorders, including pervasive developmental disorders with no obvious origin.

The compositions of the invention may be employed in the treatment of neuropsychiatric disorders and anxiety disorders, including anxiety disorders which are associated with or observed in subjects who have mental retardation, autism, Down syndrome and fragile X syndrome. Such anxiety disorders include, for example, specific phobias, such as physician and dentist phobias; agoraphobia and separation anxiety. Such disorders may also include for example, bipolar disorders, repetitive and stereotyped behavior, obsessive and compulsive traits / disorders, aggressive behavior, schizophrenia, hyperactivity, pain, itching, sensory hyperexcitability, seizures, behavioral problems, sleep disorders (including insomnia, hypersomnia and abnormal behavior during sleep).

The compositions of the invention may also be employed in the treatment of gastrointestinal disorders and metabolic disorders in subjects with mental retardation, Fragile X syndrome, Down Syndrome and autism. Autistic behavior (deficit in social interaction, verbal and nonverbal communication, and restricted / repetitive behaviors or interests) in subjects with autism, mental retardation, fragile X syndrome, and Down syndrome may also be treated by the methods of the invention. The human GABA agonist, in particular a GABA (B) agonist (eg, baclofen), may further be administered (eg, before, concomitantly, sequentially or after) with at least one member selected from the group consisting of an agonist of a nicotinic receptor, an agonist of an endocannabinoid receptor, an anticonvulsant, and an antipsychotic, an agonist of AMPA, a muscarinic antagonist M1 and an agonist of mGlur of the Group I.

The compositions of the invention may be employed in the treatment of fragile X-associated tremor / ataxia syndrome (FXTAS) and movement disorders. As discussed above, an excess of about 200 CGG repeats in the 5'-untranslated region of the FMR1 gene results in the transcriptional silencing of the FMR1 gene and the fragile X syndrome. Pre-mutation expansions (about 55 to about 200 CGG repeats in the FMR1 gene) are generally unaffected intellectually and may develop FXTAS, which is characterized by progressive cerebellar ataxia, Parkinson's, dementia, and autonomic dysfunction (Baba, Y., et al., Current Opinion in Neurology 18: 393-398 (2005).

One skilled in the art would be able to employ well-established criteria for diagnosing a subject having a mental retardation, Down syndrome, fragile X syndrome, and autism, and the conditions or deficiencies described herein. (See, for example, Patzold, L.M., et al., J. Paediatr. Child Health, 34: 528-533 (1998); Malow, B.A., Ment Retard Dev.

Res. Rev. 10: 122-125 (2004); Robinson, A.M., et al. Child

Care Health Dev. 30: 139-150 (2004); Couturier, J.L., et al. , J. Am. Acad Child Adolesc Psychiatry 44: 815-822 (2005);

Kuddo, T., et al. , Curr. Opin. Pediatr. 15: 339-343 (2003);

Molloy, C.A., et al., Autism 7: 165-171 (2003)).

Humans with fragile X syndrome treated with the methods described herein may also have autism.

In a further embodiment of the present invention, a method of treating a human comprises the step of administering to a human having at least one condition selected from a group consisting of mental retardation, Down syndrome, fragile X syndrome and autism of a composition comprising baclofen, wherein baclofen is administered to the human at a dose of about 15 mg on days 1, 2 and 3 of the treatment, a dose of about 30 mg on days 4,5 and 6 of the treatment, a dose of about 45 mg on days 7, 8 and 9 of the treatment, a dose of about 60 mg during days 10, 11 and 12 of the treatment and a dose of about 60 mg to about 80 mg daily for the duration of treatment.

In still another embodiment of the present invention, a method of treating a human comprises administering to a human having at least one condition selected from a group consisting of mental retardation, Down syndrome, fragile X syndrome and autism of a composition comprising at least about 51 mole percent of S-baclofen relative to the total of R-baclofen and S-baclofen in the composition administered to the human.

In a further embodiment of the present invention, a method of treating a human comprises administering to a human having at least one condition selected from a group consisting of mental retardation, Down syndrome, fragile X syndrome and autism , of a composition comprising at least about 51 mole percent of R-baclofen relative to the total of R-baclofen and S-baclofen in the composition administered to the human.

In still another embodiment of the present invention, the compositions of the invention allow the treatment of a human by administration to the human having at least one condition selected from the group consisting of fragile X syndrome and autism of a composition including R-baclofen (eg, at least about 99 mole percent, about 95 mole percent, about 90 mole percent, about 85 mole percent, about 80 mole percent, about 75 mole percent, about 70 mole percent, about 65 mole percent, about 60 mole percent, about 55 mole percent or about 51 mole percent of R-baclofen relative to the total R-baclofen and S-baclofen at composition administered to the human).

In a further embodiment of the present invention, the composition includes S-baclofen (eg, at least about 99 mole percent, about 95 mole percent, about 90 mole percent, about 85 mole percent, about of about 80 mole percent, about 70 mole percent, about 65 mole percent, about 60 mole percent, about 55 mole percent or about 51 mole percent of S- baclofen relative to the total of R-baclofen and S-baclofen in the composition administered to the human).

The compounds employed may be administered to a subject (e.g., before, concomitantly, sequentially or after) with administration of other compounds that are employed to treat a particular disorder or condition in the subject. For example, the compositions of the invention may be administered with at least one member selected from the group consisting of a Group II mGluR agonist, a Group II mGluR agonist, GSK33 antagonists, NAAG peptidase inhibitors, the Group mGluR antagonist I, an antidepressant, an antipsychotic, an Î ± 2 -adrenergic agonist, an anticonvulsant, a nicotinic receptor agonist, an endocannabinoid receptor antagonist, an M1 muscarinic receptor antagonist and an AMPA agonist. Glycogen synthase kinase-3 (Glycogen synthase kinase-3 (GSK3)) is an enzyme with a diverse number of actions in intracellular signaling systems, regulating neuronal plasticity, gene expression, and cell survival. GSK3p kinase is known to participate in many signaling pathways and cellular activities. GSK33 kinase is a key element of the signaling pathway through which Group I mGluR signaling regulates dendritic synaptic protein synthesis. N-acetyl-1-aspartyl-1-glutamate (NAAG) is one of the three most prevalent neurotransmitters in the mammalian brain. NAAG acts as an agonist on Group II glutamate metabotropic receptors (e.g., mGluR2, mGluR3) on neurons and glia. Specifically, NAAG activation of mGluR receptors in neurons reduces the levels of cAMP and cGMP in neurons and astrocytes. The neuropeptidases glutamate carboxypeptidase II and III (GCPII and III), also known as NAAG peptidases (hereinafter referred to as "NPs"), are metalloproteases that hydrolyze NAAG to N-acetylaspartate (NAA) and glutamate after release of NAAG in the slit synaptic. They are found in limited locations throughout the brain. Inhibition of GCPII and III increases NAAG levels, with the consequent activation of Group II presynaptic mGluRs and inhibition of transmitter release, including the release of GABA and glutamate.

A Group I mGluR antagonist (mGlurl and mGlur5) can be administered to subjects with the compounds employed in the methods of the invention.

MGluRs are a heterogenous family of G protein coupled receptors. MGluRs are classified into three groups. Group I (mGluR1 and mGluR5) receptors can be coupled to phospholipase C (PLC) stimulation resulting in phosphoinositide (PI) hydrolysis and elevation of intracellular calcium levels, ion channel modulation (eg, potassium channels, calcium, non-selective cation channels) and N-methyl-D-aspartate (NMDA). 0 mGluR5 may be present in a postsynaptic neuron. 0 mGluR1 may be present in a presynaptic neuron and / or in a post-synaptic neuron.

Group II receptors (mGluR2 and mGluR3) and Group III receptors (mGluRs 4, 6, 7 and 8) inhibit the formation of cAMP and rectifying inward potassium channels of the G protein. Group II and Group III mGluRs are negatively coupled to adenylyl cyclase, generally present in presynaptic neurons, but may be present in postsynaptic neurons and function as presynaptic autoreceptors to reduce the glutamate release of presynaptic neurons. Activation of Group II mGluRs under very high excitation of neurons may decrease the further release of neurotransmitters and stimulate the release of neuroprotective growth factors, including trophic factors, from glia.

An antagonist (eg, a Group I mGluR antagonist, a M1 muscarinic antagonist) is a substance that decreases or suppresses the effect of a ligand (eg, glutamate, acetylcholine) that activates its receptor (eg, mGluR1, mGluR5, receptor muscarinic M1). The antagonist may act at the level of the ligand-receptor interaction, such as inhibition of binding of the competitive or non-competitive ligand (e.g., allosterically). The antagonist (e.g., mGluR1 antagonist, mGluR5 antagonist, M1 muscarinic antagonist) may be, for example, a chemical antagonist or a pharmacokinetic antagonist. The antagonist, for example, may act downstream of the receptor, such as by inhibiting the interaction of the receptor with the G protein or subsequent cellular signaling events associated with G-protein activation, such as PLC activation, an increase in intracellular calcium, the production of cAMP or adenyl cyclase levels and the stimulation or modulation of ion channels (eg, potassium channels, calcium channels).

In one embodiment of the present invention, the Group I mGluR antagonist is an mGluR5 antagonist. In another embodiment of the present invention, the Group I mGluR antagonist is an mGluR1 antagonist. Suitable antagonists of Group I mGluR are described in U.S. Patent Nos .: 6,890,931 and 6,916,821. Suitable antagonists of Group I mGluR may include, for example, (E) -6-methyl-2-styrylpyridine (SIB 1893), 6-methyl-2-phenylazo-3-pyridinol, x-methyl-4-carboxyphenylglycine ( MCPG) and 2-methyl-6- (phenyltinyl) -pyridine (MPEP).

Exemplary mGluR5 antagonists for use in the methods of the invention in combination with GABA agonists, in particular GABA (B) agonists (eg, baclofen), are described in WO 01/66113, WO 01/32632, WO 01/14390, WO 01/08705, WO 01/05963, WO 01/02367, WO 01/02342, WO 01/02340, WO 00/20001, WO 00/73283, WO 00/69816, WO 00/63166, WO 00/26199, WO 00/26198, EP-A-0807621, WO 99/54280, WO 99/44639, WO 99/26927, WO 99/08678, WO 99/02497, WO 98/45270, WO 98/34907, WO 97/48399 , WO 97/48400, WO 97/48409, WO 98/53812, WO 96/15100, WO 95/25110, WO 98/06724, WO 96/15099 WO 97/05109, WO 97/05137, US 6,218,385, US 5,672,592 , US 5,795,877, US 5,863,536, US 5,880,112, US 5,902,817. Different classes of mGluR5 antagonists are described in WO 01/08705, WO 99/44639 and WO 98/34907. The antipsychotic compound employed in the methods of the invention may be a typical antipsychotic compound (also referred to as a "typical antipsychotic agent" or a "typical antipsychotic drug"). In another embodiment of the present invention, the antipsychotic compound is an atypical antipsychotic compound (also referred to as an "atypical antipsychotic agent", an "atypical antipsychotic drug" or a "second generation antipsychotic").

Exemplary atypical antipsychotic compounds for use in the methods of the invention may be at least one member selected from the group consisting of zuclopenthixol, amisulpride, aripiprazole (7- [4- [4- (2,3-dichlorophenyl) -1-piperazinyl] butoxy ] 3-4-dihydrocarbostyril), nemonapride, abaperidone (7- [3- [4- (6-fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] propoxy] -3- (hydroxymethyl) - 4H-1-benzopyran-4-one, U.S. Patent No. 5,736,588, belaperidone ((.alpha., .Alpha., .Alpha.) - 3- [2- [6- (4-fluorophenyl) -3 azabicyclo [-3.2.0] hept-3-yl] ethyl] -2,4 (1H, 3H) quinazolinedione, U.S. Patent No. 5,475,105, clozapine (8-chloro-11- (4-methyl-1-piperazinyl ) -5H-dibenzo [b, e] [1,4] diazepine, U.S. Patent No. 3,539,573, iloperidone (1- [4- [3- [4- (6-fluoro-1,2-benzisoxazol-3-yl (1-piperidinyl) -3-methoxyphenyl] ethanone, EP-402,644, olanzapine (2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3- b] [1,5] benzodiazepine, US Patent No. 5,229,382, perospirone (cis -2- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] b (2H) -dione, U.S. Patent No. 4,745,117, risperidone (3- [2- [4- (6-fluoro-1,2-benzisoxazole -3-yl) piperidino] ethyl] -2-methyl-6,7,8,9-tetrahydro-4H-pyrido [1,2-alpha] pyrimidin-4-one), U.S. Patent 4,804,663, sertindole - [2- [4- [5-chloro-1- (4-fluorophenyl-1H-indol-3-yl] -1-piperidinyl] ethyl] imidazolidin-2-one), U.S. Pat. 4,710,500; 5,112,838; and 5,238,945, thiospirone (8- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4-5] decane-7,9-dione),

U.S. Patent No. 4,411,901, ziprasidone (5- [2- [4- (1,2-benzoisothiazol-3-yl) -1-piperazinyl] ethyl] -6-chloro-1, 3-dihydro-2-one) , U.S. Patent No. 4,831,031, zotepine (2 - [(8-chlorodibenzo [b, f] thiepin-10-yl) oxy] -N, N-dimethylethanamine), U.S. Patent No. 3,704,245, quetiapine - [2- (4-dibenzo [b, f] [1,4] thiazepin-11-yl-1-piperazinyl) ethoxy] ethane-1), U.S. Patent No. 4,879,288; and blonanserin (2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydro-cycloocta [b] pyridine), U.S. Patent No. 5,021,421; U.S. 2002/0123490.

Antipsychotic agents, including atypical antipsychotic compounds for use in the invention may include, for example, Acetophenazine Maleate, Alentem, Alentejo Bromide; Alpertine; Azaperone; Batelapine Maleate; Benperidol; Benzindopyrine Hydrochloride; Brofoxine; Bromperidol; Butaclamol Hydrochloride; Butaperazine; Carfenazine Maleate; Carvotroline Hydrochloride; Chlorpromazine; Chlorprothixene; Cimperene; Cintriamide; Clomacran Phosphate; Clopenthixol; Clopimozide; Clopipazane Mesylate; Chloroperone Hydrochloride; Clotiapine; Clotixamide Maleate; Clozapine; Cyclofenazine Hydrochloride; Droperidol; Etazolate Hydrochloride; Fenimide; Flucindole;

Flumezapine; Flufenanzine decanoate; Flufenazine Enanthate; Fluphenazine Hydrochloride; Fluspiperone; Fluspirylene; Flutroline; Gevotroline Hydrochloride; Halopemide; Haloperidol; Iloperidone; Imidoline Hydrochloride; Lenperona; Loxapine; Mazapertin Succinate; Mesoridazine; Metiapine; Milenperone; Milipertin; Molindone Hydrochloride; Naranol Hydrochloride; Neflumozide Hydrochloride; Ocaperidone; Olanzapine; Oxiperomide; Penfluridol; Pentiapine Maleate; Perphenazine; Pimozide; Pinoxepine Hydrochloride; Pipamperone; Piperacetazine; Pipotiazine Palmitate; Piquindone Hydrochloride; Prochlorperazine edisylate; Prochlorperazine maleate; Promazine Hydrochloride; Quetiapine; Remoxipride; Quetiapine Hydrochloride Remoxipride; Risperidone; Risperadone Hydrochloride Rimcazole; Seperidol Hydrochloride; Serindol; Setoperone; Espiperone; Sulpiride; Thioridazine; Thiothixene; Torazina; Thioperidone Hydrochloride; Thiospirone Hydrochloride; Trifluoperazine Hydrochloride; Trifluperidol; Triflupromazine; Ziprasidone hydrochloride; analogs, derivatives and combinations thereof (see, for example, U.S. Patent Application: 2004/0019030 and U.S. 2002/0123490).

The antipsychotic compounds may have adverse side effects including, for example, central nervous system depression, weight gain, sexual dysfunction, adverse effects on mood, anticholinergic side effects (cognitive impairment, reduced memory capacity, confusion, delirium, dry mouth , blurred vision, worsening of glaucoma, constipation, urinary retention, tachycardia), weight gain, diabetes mellitus, prolactin elevation, QTC prolongation, sedation, motor side effects such as extrapyramidal symptoms (EPS), dystonia , Drug-induced Parkinson's disease, akathisia and potentially drug-induced persistent movement disorders and motor side effects such as tardive dyskinesia (see for example US publication No: 2003/0008897). These adverse side effects can reduce patient compliance and lead to relapse.

Atypical antipsychotic compounds may reduce psychotic symptoms with minor side effects (eg, extrapyramidal side effects, stiffness, tremor, akathisia, cognitive dysfunction) than typical antipsychotics (see, for example, Citrome, L., et al., Postgraduate Medicine 116: (2004)). In addition, atypical antipsychotics may also reduce aggression, repetitive behaviors, hallucinations, delusions, motivation, and emotional withdrawal. However, not all side effects (e.g., weight gain, glucose tolerance / impaired lipid abnormalities, compromised social interaction) are eliminated by the use of atypical antipsychotics. Group I mGluR antagonists have been shown to reduce weight gain and decrease appetite. Combinations of Group I mGluR antagonists and antipsychotics in the methods of the invention described herein, in particular atypical antipsychotics, may decrease or reduce the side effects of antipsychotic compounds by reducing the required dosage and increasing compliance to thereby treat subjects having conditions such as such as mental retardation, fragile X syndrome, Down syndrome, autism, pervasive developmental disorders, including pervasive disorders with no obvious origin.

The methods may further comprise a step of administering at least one member selected from the group consisting of a nicotinic receptor agonist, an endocannabinoid receptor antagonist, an AMPA agonist, an antidepressant, an antipsychotic, an α2 agonist an agonist of a nicotinic receptor, an antagonist of an endocannabinoid receptor and an AMPA agonist, which may be administered prior to, during or after administration of the Group I mGluR antagonist, antagonist of a muscarinic receptor M1 and / or the GABA (B) receptor agonist, to the human.

In one embodiment of the present invention, the GABA receptor agonist is administered (e.g., before, concomitantly, sequentially or after) the muscarinic receptor agonist M1.

In still another embodiment of the present invention, the method of treating a subject comprises the step of administering to a subject having at least one condition selected from the group consisting of mental retardation, Down syndrome, fragile X syndrome and autism, a composition comprising at least one M1 muscarinic antagonist (also referred to herein as an M1 muscarinic receptor antagonist). The muscarinic acetylcholine receptor family (mACh) consists of five members (M1, M2, M3, M4 and M5) and belongs to the G protein-coupled receptor (GPCR) receptors superfamily. A feature of GPCRs is that ligand binding, the initial step in receptor signaling, triggers a conformational change in the receptor, leading to the activation of one or more heterotrimeric G proteins. M1 muscarinic receptors may preferentially couple to PLC activation by G proteins (pertussis toxin (PTx) -insensitive G proteins) of the Gq family (Akam, EC, et al., British J. Pharmacology 132: 950 -958 (2001)).

Each muscarinic acetylcholine receptor shares common characteristics including binding specificity for the acetylcholine and carbamylcholine agonists and the classical antagonists atropine and quinuclidinyl benzylate. Each receptor subtype couples to a second messenger system via an intervening G protein. Receptors M1, M3 and M5 stimulate phosphoinositide metabolism while M2 and M4 receptors inhibit adenylate cyclase. At the tissue level, the distribution differs for each subtype. M1 receptors are found in the forebrain, especially in the hippocampus and cerebral cortex. M2 receptors are found in the heart and brain stem, whereas M3 receptors are found in the smooth muscle, exocrine glands and in the cerebral cortex. M4 receptors are found in the neoestriate and the M5 receptor mRNA is found in the substantia nigra, suggesting that M5 receptors can regulate the release of dopamine at terminals within the striatum. The activity of M1 muscarinic acetylcholine receptors M1 coupled to Gq (also referred to herein as "muscarinic M1") may regulate hippocampal-dependent learning and memory consolidation. Muscarinic acetylcholine M1 receptors (mAChRs), the major mAChRs coupled to Gq in the hippocampus, contribute to hippocampus-dependent memory.

M1 muscarinic antagonists, such as scopolamine and atropine, may abolish or decrease the action of signal transduction pathways mediated by M1 muscarinic receptors. Scopolamine and atropine are alkaloids (natural nitrogenous organic bases, which usually contain tertiary amines) from the Atropa belladonna plant. The presence of an N-methyl group in atropine or scopolamine alters the activity of the ligand, possibly by preventing a close interaction between the ligand and the membrane or lipophilic sites in the receptor. The methyl group may prevent penetration into the brain.

ATROPIN METHYL-ATROPINE

M1 muscarinic receptor antagonists (also referred to herein as "muscarinic M1 antagonists" or "muscarinic M1 antagonists") for use in the methods of the invention, in combination with the GABA agonist, in particular a GABA agonist (B), may include the following: Telenzepine is a racemic analog, more potent than Pirenzepine (Merck, Gastrozepen). Pyrenzepine does not cross the blood-brain barrier, but telenzepine can and can have reactive metabolites. The muscarinic receptor antagonist M1 (+/-) - telenzepine (about 3 mg orally at about 18 hours for about 5 days) has been used to treat chronic obstructive pulmonary disease (COPD) (chronic obstructive pulmonary disease )). The results indicate that short-term treatment with telenzapine does not improve the function of the airways in COPD patients, at least after administration by the oral route. Trihexyphenidyl (Artane), is an anti-Parkinson agent of the class of antimuscarinic agents and is chemically a tertiary amine. The drug is available as a hydrochloride salt. Benzotropin (Cogentin) (Merck) is an anticholinergic and an antihistamine. It has been used in patients with schizophrenia to reduce the side effects of antipsychotic treatment, such as Parkinson's and akathisia. Benzotropin is also a second-line drug for the treatment of Parkinson's disease. This drug improves tremors but not stiffness or bradykinesia. Benzotropin is also sometimes used in the treatment of dystonia, a rare disorder that causes abnormal muscle contractions, resulting in limb, trunk, or face torsion postures. Dicyclomine (Bentyl) has been used in the treatment of intestinal hypermotility, symptoms of Irritable Bowel Syndrome (Irritable Bowel Syndrome). This drug relieves muscle spasms in the gastrointestinal tract by blocking the activity of a certain natural substance in the body. It is a smooth muscle relaxant. Bentyl is also referred to as Byclomine, Dibent, Di-Spaz, Dilomine, Bentylol (Hoechst Marion Roussel), Formulex (ICN) and Lomine (Riva). Biphenyl-2-enyl) -1-phenyl-3- (1-piperidyl) propan-1-ol) Biperidene is an anticholinergic anti-Parkinson agent and is also referred to as Akineton® (BASF / Knoll Pharma). Procyclidine (1-cyclohexyl-1-phenyl-3-pyrrolidin-1-yl-propan-1-ol hydrochloride) has been used in the treatment of schizophrenia to reduce the side effects of antipsychotic treatment such as Parkinson's and akathisia. Procyclidine is also a second-line drug for the treatment of Parkinson's disease and may improve tremors, but not stiffness or bradykinesia. Procyclidine may be employed in the treatment of dystonia (but not tardive dyskinesia), a rare disorder that causes abnormal muscle contractions, resulting in limb, trunk, or face torsion postures. (1R, 2R, 4S, 7S, 9S) -9-methyl-3-oxa-9-aza-tricyclo [3.3.1.02 , 4] non-7-yl ester) acts as a competitive antagonist on specific acetylcholine muscarinic receptors (the M1 receptor). Scopololamine is classified as an anticholinergic, or, more specifically, an antimuscarinic drug. Ipratropium quaternary muscarinic antagonist, and tiotropium, of long duration, may also be employed.

Ipatropion Tiotrope

Enantiomerically enriched compositions (+, R, S; d, 1) (eg, about 99 mole percent, about 98 mole percent, about 95 mole percent, about 90 mole percent, about 85 percent molar, about 80 percent molar, about 75 percent molar, about 70 percent molar, about 65 percent molar, about 60 percent molar, about 55 percent molar, about 51 percent of an enantiomer in the composition relative to the total of both enantiomers in the composition) of the muscarinic antagonists M1 in the methods described herein.

The methods may further comprise the step of administering a stimulant to the subject. "Stimulant" as used herein refers to any compound that promotes or enhances wakefulness, alertness, physical activity, improves cognition, improves learning, or reduces fatigue. Stimulants for use in the invention may (eg, d, 1, R, S) or derivatives thereof. The stimulant used in the methods described herein may antagonize the receptor of the compound of formula (I). adenosine, inhibit dopamine uptake, antagonize the H 3 receptor, promote dopamine release, inhibit moniamine oxidase in the nervous system (the central nervous system, peripheral nervous system, and autonomic nervous system) or any combinations thereof.

The compounds employed may be administered to a subject administered (e.g., before, concomitantly, sequentially or thereafter) with other compounds employed in the treatment of a particular disorder or condition in the subject. For example, the compositions of the invention may be administered with at least one member selected from the group consisting of an antidepressant, a Group I mGluR antagonist, a M1 muscarinic antagonist, an antipsychotic, an? 2 adrenergic agonist and an anticonvulsant. Identification of suitable compounds, such as antidepressants, antipsychotics, Î ± 2 adrenergic agonists, anticonvulsants, a nicotinic receptor agonist, an endocannabinoid receptor antagonist and AMPA agonists, for use in the methods of the invention would be well known to a person skilled in the art. (see, for example, Beryy-Kravis, E., et al., Mental Retardation and Developmental Disabilities 10: 42-48 (2004)).

The compounds employed in the invention may be administered to the subject acutely (briefly or short term) or chronically (prolonged or long term). For example, the compounds may be administered to subjects for days (1-7), months (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), years , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) or during its lifetime.

Subjects treated by the invention may have at least one condition selected from the group consisting of a sensory hyperexcitability disorder, an anxiety disorder, a seizure disorder, a gastrointestinal disorder, a sleep disorder, an aggressive or aberrant behavior, and a deficient cognitive function.

The subjects treated by the invention may also have at least one condition selected from a group consisting of an abnormality in social interaction, interests and repertoire of limited behaviors and a condition of social avoidance.

The subjects (eg, humans, also referred to herein as "patients") treated by the invention may have a cognitive deficiency, such as reaction time deficiency, ocular monitoring, motor coordination, gait, oral-motor function, communication, attention, executive function, reaction time, learning, information processing, conceptualization, problem solving, verbal fluency or memory (eg, memory consolidation, short term memory, working memory, long term memory, declarative memory or memory procedural). Deficiency in a cognitive function treated by the methods described herein may be a deficiency in attention, which is the ability or process of selection, from the totality of available sensory or affective stimuli, of the stimuli that are most appropriate or desirable to be focused on a given (Kinchla, RA, et al., Annu Rev. Psychol 43: 711-742 (1992)). Deficiency in the cognitive process may be a deficiency in the executive function, which is neuropsychological functions such as decision making, planning, initiative, prioritization, sequencing, motor control, emotional regulation, inhibition, problem solving, planning, impulse control, goal setting, results monitoring and self-correction (Elliott, R., Br. Med. Bull. 65: 49-59 (2003)). Cognitive impairment can be a deficiency in alertness, alertness, arousal, vigilance, and reaction time in information processing, conceptualization, problem solving, and / or verbal fluency. One skilled in the art would be able to identify and assess deficiency in a cognitive function in the individual.

An "effective amount," also referred to herein as a "therapeutically effective amount", when referring to the amount of a compound or a composition (eg, baclofen, a muscarinic receptor antagonist M1) is defined as the amount, or dose, of a or a composition which, when administered to a subject, is sufficient for therapeutic efficacy (eg, a sufficient amount of decrease to exhibit a clinical improvement in the behavior or outcome of a cognitive mental test, alleviate a sensory hyperexcitability disorder, a an anxiety disorder, a seizure disorder, a gastrointestinal disorder, a sleep disorder, prevent weight gain, decrease obsessive compulsive tendencies and behaviors.

The methods may be performed by administering the compounds of the invention (e.g., compositions including baclofen) by enteral or parenthetic means. The route of administration may be oral (e.g., tablet, capsule form) or intramuscular injection of the compound. Other routes of administration may include intravenous, intraarterial, intraperitoneal, or subcutaneous routes, nasal administration, suppositories and transdermal patches.

In one embodiment of the present invention, the compounds (e.g., baclofen, Group I mGluR antagonists, M1 muscarinic receptor antagonists) may be administered at a dose of from about 0.01 mg / kg to about 0.1 mg / kg; about 0.001 mg / kg to about 0.01 mg / kg; about 0.001 mg / kg to about 0.05 mg / kg; about 0.1 mg / kg to about 1 mg / kg body weight; about 1 mg / kg to about 5 mg / kg body weight; or from about 5 mg / kg to about 15 mg / kg body weight.

The compounds may be administered at doses of about 0.1 mg, about 1 mg, about 2 mg, about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 80 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 900 mg, about 1000 mg, about 1200 mg, about 1400 mg, about 1600 mg or about 2000 mg, or any combination thereof. The compounds may be administered once or multiple (e.g., two, three, four, five) times per day.

In still another embodiment of the present invention, the compounds employed in the methods of the invention are administered to about 1 mg BID (twice daily), about 2 mg BID, about 3 mg BID, about 5 mg BID mg BID, about 10 mg BID and about 10 mg TID (three times a day).

In another practical embodiment of the present invention, the compounds may be administered in a dosage regimen which includes progressive or increasing increases of the compound over the course of the treatment time. For example, a subject may be treated with baclofen (e.g., R-baclofen, such as between about 20 to about 40 mg per day) at a dose of about 2 mg / day on days 1, 2 and 3 of the treatment; about 4 mg / day on days 4, 5 and 6 of the treatment; about 6 mg / day on days 7, 8 and 9 of the treatment; about 20 mg / day on days 13, 14 and 15 of the treatment and about 30 mg / day on days 16, 17 and 18 of the treatment.

The compounds of the invention may be administered to the human at a selected dose (eg, a dose of about 10 mg taken 3 times a day or a dose of about 15 mg given while three doses of about 5 mg each) while monitoring improvements in the human (eg, cognition, behavior). If the human shows no improvement, the compositions employed in the methods may be increased, decreased or discontinued until a beneficial effect is observed. For example, if the treatment started with three (3) doses of about 10 mg daily and the human subsequently exhibited no apparent improvement, the dose may be increased to three (3) doses of about 15 mg per day, decreased to two (2) doses of about 10 mg per day or the treatment may be discontinued for a single dose, a number of days or weeks, and subsequently initiated after the "mini-drug vacations".

"Drug mini-vacations" as used herein refers to the removal of the human from the treatment or a decrease in the dosage of the compound, followed by reintroduction of the treatment, at a dose equivalent to, less or in excess of the dose the received before the mini-vacation of the drugs.

In still another embodiment of the present invention, the method of treating a human comprises the step of administering to a human having at least one condition selected from the group consisting of Down syndrome, fragile X syndrome and autism , a composition comprising baclofen, wherein baclofen is administered to the human at a dose of about 2 mg per day on days 1, 2 and 3 of the treatment, a dose of about 4 mg per day on days 4, 5 and 6 of the treatment, a dose of about 6 mg per day on days 7, 8 and 9 of the treatment, a dose of about 10 mg per day on days 10, 11 and 12 of the treatment, a dose of about 20 mg per treatment. day on days 13, 14 and 15 of the treatment, a dose of about 30 mg per day on days 16, 17 and 18 of the treatment and a dose of about 15 mg to about 80 mg per day for the duration of treatment or between about 30 mg to about 80 mg per day for the duration of the treatment.

In a further practical embodiment of the present invention, the method of treating a human comprises the step of administering to a human having at least one condition selected from the group consisting of Down syndrome, fragile X syndrome and autism, a composition comprising baclofen, wherein baclofen is administered to the human in a dosage regimen of at least one member selected from a group consisting of about 1 mg twice daily, about 2 mg twice daily, about of 3 mg three times a day, about 5 mg twice daily, about 10 mg twice daily, and about 10 mg three times a day.

One skilled in the art can adjust the doses of the compounds to be used in the methods. A suitable dose of a compound (e.g., GABA agonist (B), such as baclofen, muscarinic receptor antagonist M1) for use in a subject may be a titrated dose. For example, the subject would initially receive a low dose, doses would be increased if the low dose was not effective. Doses could be increased to about every 3-7 days of treatment, with adjustments as needed based on side effects. Doses may be titrated up to the maximum tolerated dose or until the determination of the maximally effective dose. Subjects may be maintained at the maximum tolerated or maximally effective dose.

In one embodiment of the present invention, baclofen administered to the human is a racemic mixture (50 mole percent of R-baclofen and 50 mole percent of S-baclofen). In a further embodiment of the present invention, the baclofen administered to the human is enriched for one of the enantiomers of baclofen. The enantiomerically enriched baclofen may include a composition that is at least 51 mole percent, at least 55 mole percent, at least 60 mole percent, at least 65 mole percent, at least 70 mole percent, at least 75 percent at least 90 mole percent, at least 90 mole percent, at least 90 mole percent, at least 90 mole percent, at least 90 mole percent, at least 90 mole percent, at least 90 mole percent, at least 90 mole percent, -baclofen with respect to the total amount of R-baclofen and S-baclofen in the composition administered to the human.

Alternatively, the enantiomerically enriched baclofen may include a composition that is at least 51 mole percent, at least 55 mole percent, at least 60 mole percent, at least 65 mole percent, at least 70 mole percent, at least 75 mole percent, at least 85 percent molar, at least 90 percent molar, at least 90 percent molar, at least 95 percent molar, at least 98 percent molar, at least 99 percent molar, or 100 percent molar of S-baclofen relative to the total amount of S-baclofen and R-baclofen in the composition administered to the human.

The compounds of the invention may be administered alone or can be coadministered to the patient. Coadministration is intended to include simultaneous or sequential administration of one or more compounds (e.g., baclofen and a muscarinic receptor antagonist M1) employed in the methods of the invention individually or in combination. The mode of administration may be conducted sufficiently closely in time between each other so that the effects on the subject are maximal. Also provided is the possibility of using multiple routes of administration (e.g., intramuscular, oral, intranasal, inhalation, topical, transdermal) for administration of the compounds employed in the methods of the invention.

The compounds of the invention may be administered alone or in admixture with conventional excipients, for example, pharmaceutically or physiologically acceptable organic or inorganic carrier substances suitable for enteral or parenteral application which do not detrimentally react with the compound (s) administered to the subject. Suitable pharmaceutically acceptable carriers include water, saline solutions (such as Ringer's solution), alcohols, oils, gelatin and carbohydrates such as lactose, amylose or starch, esters of fatty acids, hydroxymethylcellulose and polyvinylpyrrolidine. Such preparations may be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, osmotic pressure influencing influences, buffers, colorants and / or aromatic substances and the like which do not adversely affect with the compounds used in the methods of the invention. The preparations may also be combined, when desired, with other active substances to reduce metabolic degradation. A preferred method of administering the compounds employed in the methods of the invention may be oral administration, such as in tablet form.

The compounds of the invention, either alone or when combined with a mixture, may be administered in a single dose or at more than one dose over a period of time that confers the desired effect (eg, alleviating autism symptoms, improving the patterns of sleep, decrease the disturbance of sensory hyperexcitability, alleviate an anxiety disorder, a seizure disorder, a gastrointestinal disorder, poor cognitive function, weight gain).

When a parenteral application is necessary or desirable, blends particularly suitable for the compounds employed in the methods of the invention are injectable, sterile solutions, preferably oily or aqueous solutions, such as emulsions or implants, including suppositories. In particular, carriers for parenteral administration include aqueous solutions of dextrose, saline solutions, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, and the like. Ampoules are convenient dosage units. The compounds for use in the methods of the invention may also be incorporated into liposomes or administered by transdermal patches or patches. Suitable pharmaceutical mixtures for use in the present invention are well known to those skilled in the art and are described, for example, in Pharmaceutical Sciences (17th Ed., Mack Pub. Co., Easton, PA) and WO 96/05309. Dosage and frequency (single dose or multiple doses) administered to an individual may vary depending upon a variety of factors, including the duration of the subject's condition (eg, sensory hyperexcitability disorder, anxiety disorder, seizure disorder, gastrointestinal disorder, sleep disturbance, poor cognitive function, weight gain, obsessive compulsive behaviors); the route of administration of the compound; size, age, sex, health, body weight, body mass index, and diet of the recipient; (eg, sensory hyperexcitability disorder, anxiety disorder, seizure disorder, gastrointestinal disorder, sleep disorder, impaired cognitive function), type of concomitant treatment (eg, behavioral modification, antidepressants, α2-adrenergic agonists, anticonvulsants, a nicotinic receptor agonist, an endocannabinoid receptor antagonist, AMPA agonists, antipsychotics), complications derived from, for example, a sensory hyperexcitability disorder, an anxiety disorder, an seizure disorder, a gastrointestinal disorder, a sleep disorder or poor cognitive function; or other health-related problems. Other therapeutic regimens or agents may be used in conjunction with the methods of the present invention. For example, administration of compounds of the invention may be accompanied by behavioral modifications, antidepressant medications and antipsychotic medications. Adjustment and manipulation of the stated dosages (e.g., frequency and duration) are well within the capabilities of those skilled in the art.

A further embodiment of the present invention is the use of compositions and compounds (eg, baclofen, muscarinic receptor agonists M1, Group I mGluR antagonists) for the manufacture of a medicament for treating subjects (eg, humans) having the conditions described herein (eg, fragile X syndrome, autism).

Another practical embodiment of the present invention is a pharmaceutical composition comprising the compositions and compounds described herein (eg, baclofen, M1 muscarinic receptor agonists, Group I mGluR antagonists) to treat subjects having the conditions described herein (eg, fragile X syndrome, autism).

The following is a description of examples of practical embodiments of the present invention.

EXEMPLIFICATION

EXAMPLE 1: TREATMENT OF BACLOFEN AUTISM

A 23-year-old woman with autism spectrum disorders (height 61 '', weight of 170 pounds) was hospitalized and was prepared for placement of a catheter to initiate TPN for an indeterminate period of time in order to allow total rest intestine. Baclofen was prescribed at a dosage of 5 mg tid (three times a day) to improve intestinal motility. Within 24 hours, abdominal pain seemed to be resolved and gastrointestinal motility became functional, allowing for oral feeding. Over the next days and weeks, improvements were observed in cognitive and behavioral domains that had remained unchanged for more than 10 years.

For example, improvements in social interaction, as evidenced by a. Greater interest and increased response to spoken language b. Increased spontaneous attempts at interaction c. Increased joint attention and eye contact; improvements in motor coordination, as evidenced by a. much improved oral motor b. improved engine planning c. improved gait; improvements in communication, as evidenced by a. immediate and appropriate responses to spoken language (receptive language) b. increase of verbal language ("No" "OK" "go") and attempts to approximate words c. increased spontaneous use of augmentative communication device; Dramatic improvements in mood and affection "seems comfortable, calm and happy"; greater interest and motivation to work in cognitive / educational activities; physical strength and energy greatly improved; increase in the repertoire of age-appropriate behaviors and interests.

After about 3 weeks of baclofen (about 5 mg tid), the beneficial effects began to decrease. At that time, the dose was increased to about 10 mg tid, but the increase in dosage did not produce the above beneficial effects. A single dose of about 15 mg produced the typical side effects of sedation. An alternative dosing regimen included omission of the overnight dose for one day (eg, mini-drug vacations) followed by resumption of the original dose (about 5 mg tid) the next day, which resulted in beneficial effects in the cognitive domains and behavioral, as described above. Efficacy has been observed for about 11 weeks in the present at a dose of about 10 mg bid (twice daily). When the positive effects begin to decrease, a single dosage is missing and the complete efficacy is again observed. During the first two months, it was necessary to skip a dose at about once every 5-7 days to maintain overall effectiveness, this interval having been recently increased to once every 10-14 days.

Improvements were observed in domains that had remained unchanged or stable for more than 10 years (eg, communication, verbalization, joint attention, socialization, coordination), with maximum benefits occurring at lower doses than those typically effective for treatment of gastrointestinal spasticity (the approved indication), the observed improvements correlated with the specific dosage range, and tolerance to beneficial effects was not rescued by increased dosage but was repeatedly rescued by omission of a single dose.

This 23-year-old woman was taking the following medications at the time she started treatment with baclofen: - 175 mg of topamax: pain and history of 4 major seizures (none since 2002); - 30 mg of prevacid bid; 150 mg zantac tide; - 8 mg zofran every 8 hours to treat chronic vomiting; - 500 mg magnesium Philips tid to treat constipation; - ducolax as needed for constipation; - 100 mg tramadol as needed (every 6-8 hours); and oxycodone for disruptive pain

This 23-year-old woman underwent an amitriptyline assay for 3 days in the hospital, without effect, prior to baclofen treatment. Tramadol and oxycodone intake were discontinued when baclofen was started. Over the past few weeks, the dose of many of the above drugs has been gradually reduced. Your current medications are: - baclofen 20 mg (10 mg twice daily); topamax 125 mg; and zantac 150 mg.

EXAMPLE 2: TREATMENT OF BACLOFENE AUTISM

A 12-year-old boy with autism spectrum disorders (height = 54 ", weight = 64 lbs) was treated with baclofen. Baclofen (about 5 mg bid) was initially given in an attempt to reduce symptoms of gastroesophageal reflux. Over the next days and weeks, improvements have been observed in various cognitive and behavioral domains, such as increased interest and response to spoken language and attempts to communicate verbally. Dramatic improvements in mood and affection, such as "looks comfortable, calm and happy" were also observed. Greater attention, interest and motivation were also observed to work on cognitive / educational activities with school instructors. School officials record behavior on a daily basis, are not informed of changes in drug treatment, and were unaware that baclofen had been prescribed for this subject. Daily scores were averaged over 5 weeks after initiation of baclofen therapy and compared to mean scores five weeks prior to initiation of baclofen therapy.

Significant improvements were observed after initiation of baclofen therapy in the following domains:

The episodes of scratching, hitting and kicking others decreased from an average of 17 + 2 (mean + standard error) to 6 + 1 episodes per day.

Episodes of biting hands or head banging have decreased from an average of 15 + 2 to 6 + 1 episodes per day. - The episodes of deviation of the eyes decreased from an average of 10 + 2 to 5 + 2 episodes per day.

These benefits were maintained for 5 weeks at a stable dosage of 5 mg bid.

Concomitant medicinal products at the time of initiation of baclofen therapy: - Tegretol 800 mg / day for a history of 4 major seizures - Prevacid 30 mg bid - Lamotrigine 25 mg / day - Singulair 5 mg / day - Carafate 1 mg bid

EXAMPLE 3: TREATMENT OF BACLOFEN AUTISM

A 9-year-old boy with autism spectrum disorders (height = 46 ", weight = 47 pounds) was treated with baclofen. Baclofen (about 5 mg bid) was initially given in an attempt to reduce symptoms of gastroesophageal reflux. Over the next days and weeks, improvements in cognitive and behavioral domains were observed, such as increased interest and response to spoken language and spontaneous attempts at communication. Parents also noted an improvement in sleep, mood, and affect patterns. Greater attention, interest and motivation were also observed to work on cognitive / educational activities by school officials. School officials record behavior on a daily basis, are not informed of changes in drug treatment, and were unaware that baclofen had been prescribed for this subject. Daily scores were averaged over 5 weeks after initiation of baclofen therapy and compared to mean scores of five weeks prior to initiation of baclofen therapy. Improvements were observed in the frequency of startle / tremor activities, which are thought to reflect brief seizure activities (duration of approximately 2 seconds) in this subject. After initiation of baclofen treatment, episodes of startle and tremor decreased from an average of 66 + 24 (mean + standard error) to 16 + 5 episodes per day. Similarly, the incidence of spontaneous attempts at communication increased from an average of 11 + 1 to 21 + 2 episodes per day.

These benefits were maintained for 5 weeks at a stable dosage of 5 mg bid.

Concomitant medicinal products at the time of initiation of baclofen therapy: - Tegretol 800 mg / day for a history of seizures - Prevacid 30 mg bid - Lamotrigine 50 mg / day - Singulair 10 mg / day

EXAMPLE 4: TREATMENT OF A DISTURBANCE OF THE BACLOFEN AUTISM SPECTRUM

Racemic Baclofen was administered to 21 (21) subjects (12 men and 9 women) with autism spectrum disorders (see Table 1). Subjects had severe behavioral problems that were not controllable with a variety of medications, including antiepileptics (N = 14), antipsychotics (N = 8), and antidepressants (N = 6). The doses of baclofen administered to the subjects were titrated on a weekly basis of about 2.5 mg twice daily (BID) to a maximum of about 15 mg three times a day (TID), with a maximum treatment duration of about 8.5 months. The clinician evaluated the overall impression of improvement with baclofen treatment on a seven-point scale ranging from "much worse," "worse," slightly worse, "unchanged," slightly better "," better "or" much better " The subjects receiving baclofen were considered to have improved if the clinical evaluation was "much better" or "better." Similarly, treatment with baclofen was considered not to have improved the subject's condition if the clinical evaluation was "slightly worse," "unchanged," or "slightly better." If a subject worsens with baclofen treatment, the clinical evaluation would be "worse" or "much worse."

Eight (8) of the 21 subjects demonstrated improvements in the presented symptoms, including less irritability / aggressiveness, better communication or better social interaction. Other areas of improvement included increased class participation and decreased hyperactivity. Eleven (11) subjects did not improve and two (2) subjects worsened. Eight (8) subjects did not continue treatment with baclofen. These included 2 patients who did not improve, 1 patient who improved but did not continue treatment, 3 patients who discontinued treatment for unrelated reasons, and 2 who had adverse side effects considered to be related to the initiation of baclofen treatment (somnolence in one hyperactivity in the other). Other adverse effects included difficulty sleeping, otitis, increased gastrointestinal discomfort / soft stools, and increased self-stimulation with fingers. Racemic baclofen has been used to treat spasticity and has a well-defined safety profile in adults and children. There is no reason to prescribe baclofen for children with brain developmental disorders. In patients with fragile X syndrome, doses of racemic baclofen were titrated from an initial dose of about 2.5 or about 5 mg BID to a maximum of about 20 mg TID, with a maximum duration of 4 months. Two out of five patients demonstrated an improvement in behavior including less irritability, aggressiveness and agitation, two were still in titration and the treatment was discontinued in a subject who developed drowsiness and irritability when the dose was increased to about 20 mg / day. Other areas of improvement included increased class participation and decreased hyperactivity. Of note, all patients with fragile X syndrome (Example 5) were receiving psychoactive drugs and four of the five patients were receiving concomitant treatment with atypical antipsychotics. In patients with idiopathic autism, doses were titrated from about 2.5, 5 or 10 mg BID to a maximum of about 15 mg TID, with a maximum duration of 8.5 months. Eight of the 21 patients demonstrated improvements in the symptoms presented, including lower irritability / aggressiveness, better social communication / interaction, and a lower frequency and severity of gastrointestinal symptoms. Other areas of improvement included increased class participation and less hyperactivity. Baclofen treatment was discontinued in eight patients, including one who improved, five who did not improve and two patients who worsened (increased hyperactivity in both). Of note, these patients were commonly receiving treatment with psychoactive drugs (N = 14), antipsychotics (N = 8) and antidepressants (N = 6). The overall impression was that baclofen was particularly useful in the treatment of irritable and aggressive behavior.

Table 1: Treatment with Baclofen in Patients with Autism Spectrum Disorders

Overall impression of improvement with Baclofen by the clinician: Improved includes "much better" and "better"; Not improved includes "slightly better" and "no change"; Piorou includes "worse" and "much worse"

EXAMPLE 5: FRAGILE X SYNDROME

Racemic Baclofen was administered to treat five (5) male subjects with Fragile X syndrome (Table 2). These subjects had severe behavioral problems that were incompletely controlled with typical psychoactive medications. Baclofen was added to the concomitant antipsychotic treatment in four (4) of the five (5) subjects. Doses were titrated from about 2.5 mg BID to a maximum of about 20 mg TID, with a maximum duration of about 4 months. Clinicians rated the overall impression of improvement with baclofen treatment on a seven-point scale ranging from "much worse," "worse," slightly worse, "unchanged," slightly better "," better "or" much better " Were considered "Improved" if the clinical evaluation was "much better" or "better", considered "Not Improved" if the evaluation was "slightly worse", "unchanged" or "slightly better"; as "worse" if the assessment was "worse" or "much worse." Two of the 5 patients demonstrated improved behavior, including decreased irritability, aggressiveness, and agitation.Additional areas of improvement included increased class participation and hyperactivity Two subjects did not show obvious improvements and the dosage regimen was still being adjusted. One subject worsened as evidenced by excessive drowsiness, increased irritability, shouting and prague baclofen was discontinued.

Table 2: Treatment with Baclofen in Fragile X Patients

Overall impression of improvement with Baclofen by the clinician: Improved includes "much better" and "better"; Not improved includes "slightly better" and "no change";

Piorou includes "worse" and "much worse" EXAMPLE 6: TREATMENT OF KNOCKOUT X FRAGILE MURGAS WITH A GABA AGONIST (B)

Racemic Baclofen Commercially available baclofen (Sigma Chemical Co., St. Louis, Mo) is a 50:50 racemic mixture of Re S isomers. In order to better understand the binding affinity of racemic baclofen, the Secondary Effects Database (Side Effect Database (SED)) was licensed by Novascreen Biosciences Corporation (Hanover, MD). The side-effects database includes 76 molecular targets screened against 10 μΜ of racemic baclofen in duplicate. These targets may be key mediators of baclofen side effects, off-target effects and therapeutic targets. According to the Secondary Effects Database, baclofen is selective for GABA-B and less than about 50% binding at 10 μΜ over the other 75 molecular targets.

The experiments described herein in these preclinical studies demonstrate the efficacy of racemic baclofen in a wide range of pharmacological, physiological and behavioral assays. Racemic baclofen reduces burial behavior of berlinds in Fmrl knockout mice (Figure 1). Berber burial behavior is accepted as reflecting related anxiety and obsessive / compulsive and persevering responses and, as such, mimics the symptoms commonly observed in subjects with fragile X syndrome and other disorders of brain development. R-baclofen R-baclofen is a more potent agonist of GABA-B than the S-isomer. The binding affinity for R- isomers (about 99% R-baclofen) and S- (about 99% S-baclofen) from baclofen (purchased from Sigma Chemical Co., St. Louis, MO) was evaluated. Both R- and S-baclofen were evaluated at 10 μg in duplicate against 74 molecular targets (29 targets related to neurotransmitters, 1 steroid, 3 ion channels, 1 secondary messenger, 4 growth factors / hormones, 13 brain / intestine, 12 general enzymes, 9 kinases and 2 functional and cell-based targets). Tests have confirmed that R- and S-baclofen are selective agonists of GABA-B and also that the R-isomer is a more potent GABA-B agonist than the S-isomer (Table 3). As shown in Table 3, GABA binding assays (B) were performed using rat cortical membranes. IC 50 and Ki values indicate that R-baclofen is about 10 to about 15 times more potent than S-baclofen and that R- / S-baclofen has an intermediate potency.

Table 3

The dose-response ratios for racemic (R- / S-) baclofen and for each of the isomers alone (R- or S-baclofen) in the burial behavior of berlindes were evaluated. R-baclofen was more potent than S-baclofen as an inhibitor of burial behavior of berlinds (Figures 2 and 3). Berlind burial behavior is accepted as reflecting related anxiety and obsessive / compulsive and persevering behaviors and, as such, mimics the symptoms commonly observed in subjects with Fragile X syndrome (FXS) and other disorders of brain development. R-baclofen is more potent for the inhibition of audiogenic seizures of S-baclofen (Figure 4). An increased susceptibility of audiogenic seizures in Fmrl knockout (KO) mice is accepted as modeling the increased prevalence of seizure disorders in subjects with fragile X syndrome.

BERLINDES ENTERTAINMENT TEST

Experimental objective The aim of the experiment was to determine whether berber burial behavior is reduced after administration of the GABA-B receptor agonist B-baclofen and / or S-baclofen. In these experiments, Fmr KO mice received an intraperitoneal injection of R-baclofen or S-baclofen and were tested for burial behavior of berlinds.

Results

The results of the experiment demonstrate that R-baclofen and S-baclofen alter the berlind burial behavior in Fmrl KO mice. There was a significant dose dependent change in burial behavior of berlinds in Fmrl KO mice which received an intraperitoneal injection of R-baclofen 1 hour before the test. Specifically, Fmr KO mice receiving a dose of 10 mg / kg buried significantly less berlinds than mice receiving 0, 0.3, 1, 3, or 6 mg / kg. There was also a significant dose-dependent change in burial of berlinds in Fmrl KO mice that received an intraperitoneal injection of S-baclofen 1 hour before the test. Specifically, mice given a dose of 1 mg / kg buried significantly more berlinds than mice receiving 0.0 mg / kg. In addition, mice receiving 50 mg / kg buried fewer beryls than mice receiving 0, 0.3, 1, 6 or 30 mg / kg S-baclofen.

Conclusions

The results of this experiment indicate that there is a dose-dependent reduction in burial behavior of berlinds in R-baclofen-treated Fmrl KO mice indicating that R-baclofen reduces the anxiety / obsessive / repetitive type behaviors evaluated in this assay. In addition, S-baclofen altered the burial behavior of berlinds in a dose-dependent manner, however, at the dose of 1 mg / kg, Fmrl KO mice actually buried more berlinds, suggesting that this dose may have a opposite to the desired effect. Fmr KO mice receiving a dose of about 50 mg / kg buried fewer beryls, indicating that this high dose reduces these anxiety / obsessive / repetitive type behaviors evaluated in this assay. These data indicate that R-baclofen may be more suitable than S-baclofen for the reduction of these anxiety / obsessive / repetitive behaviors simulated by the burial test of berlindes.

Mice Fragile (Fmrl), Knock Out (KO)

Fmrl KO mice on a C57BL / 6J gene pool (9 generations) were supplied by The Jackson Laboratory (Bar Harbor, ΜΕ). The C57BL / 6J gene pool was backcrossed to establish N11 generation Fmrl mice. All mice for the current study were generated by crossing Fmrl heterozygous female mice with wild-type male mice. Only Fmrl KO males (Fmrl / y) were tested in this study. Twelve mice per cage were housed in a room with a light / dark cycle of 12 hours (lights switched on from 6 in the morning and turned off at 6 o'clock in the afternoon) with access to food and water ad libitum. Male mice 2-4 months old (20-30 grams) were used for all experiments. In general, the behavioral test was performed between 9 am and 3 pm. At the start of the test, the mice were 3-4 months old. One experimenter blinded to mouse genotypes performed the experiments.

The animals were genotyped by standard PCR techniques. For the detection of the Fmrl WT allele (product with 527pb), PCR was performed on Tailed DNA with primers Fmrl_Sl (5'GTGGT 7AGCTAAAGTGAGGATGAT-3 '; SEQ ID NO: 1) and Fmrl_S2 (5'CAGGTfTGTTGGGATTAACAGATC-3'; SEQ ID NO: 2). The Fmrl KO allele (501bp product) was detected by PCR with primer Fmr1S1 and primer Fmr1N2 (5TGGGCTCTATGGCTTCTGA-3 '; SEQ ID NO: 3) which binds to a Neo cassette that replaces exon 5 of the Fm1 gene. The thermal cycling conditions were identical for both S1 / S2 and S1 / N2: 2 min at 94 ° C, 30 sec at 55 ° C, 60 sec at 72 ° C), 10 min at 72 ° C using reagents of standard PCR. Methods

A standard mouse cage was filled with 10 cm of stratum of corn cobs. Twenty (20) small (1.5-2 cm) black berlinds were placed equidistantly (about 1-2 cm between them) on top of the bed. A mouse was placed in the cage allowing it to explore and burial the berlindes. After about 20 minutes, the mouse was removed and the number of marbles buried (a berlinde is considered to be "buried" if more than 50% of this is found underneath the stratum).

Baclofen and placebo were given to the mouse one hour prior to training by intraperitoneal (i.p.) injections in a volume of 0.1 ml / 10 mg body weight.

Mice were injected (i.p.) with a dose of R (+) - or S (-) - baclofen one hour prior to the test. Each mouse was injected with a dose of R or S prior to the test. The order of the treatment (e.g., R followed by S, or S followed by R) was equilibrated, and the dose was randomly assigned to each drug. There were at least 3 days between the tests.

At the time of the test, a mouse was placed at one end of the cage containing the berlindes, allowing him 20 minutes to burrow berlinds. After the 20 minute test, the mice were removed and the buried berlinds counted. A berlinde was identified as being "buried" if at least 50% of this is covered in stratum. After the test, the mice were returned to their home cages. The following numbers (N) of mice were used for the various doses of R (+) -baclofen: N = 16.0 mg / kg; N = 15, 0.3 mg / kg; N = 15, 1.0 mg / kg; N = 10, 3.0 mg / kg; N = 13, 6.0 mg / kg; N = 10, 10 mg / kg. The following numbers (N) of mice were used for the various doses of S (-) - baclofen: N = 15.0 mg / kg; N = 13, 0.3 mg / kg; N = 14, 1.0 mg / kg; N = 12, 6.0 mg / kg; N = 11, 30.0 mg / kg; N = 14, 50 mg / kg.

Buried berlinds were counted manually on a data sheet by a blind experimenter regarding genotype and treatment. The data was then manually entered into a computer table.

Data were analyzed with bidirectional ANOVA (dose X treatment order). Significant significant dose effects were then analyzed using least squares follow-up comparisons. Statistical analyzes were analyzed using SPSS 11.0 software.

Results

Baclofen Racemic Administration of racemic baclofen (6 mg / kg, 12 mg / kg) to fragile X knockout mice reduced berlind burial behavior in a dose-dependent manner (Figure 1). Figure 2 shows that there was a significant dose-dependent change (p <0.005) in burial behavior of berlinds in Fmrl KO mice that received an intraperitoneal injection of R-baclofen one hour before the test. Specifically, Fmr KO mice receiving a dose of 10 mg / kg buried significantly fewer (p <0.05) berlings than mice receiving 0, 0.3, 1, 3 or 6 mg / kg. The effect of the treatment order was not statistically significant (p> 0.05). Figure 3 shows that there was also a significant dose-dependent change (p <0.005) in burial behavior of berlinds in Fmrl KO mice that received an intraperitoneal injection of S-baclofen one hour before the test. Specifically, mice given a 1.0 mg / kg dose buried significantly more (p <0.05) beryl counts than did mice receiving 0.0 mg / kg. In addition, mice receiving a dose of 50 mg / kg buried significantly less (p <0.05) berlings than mice receiving 0, 0.3, 1, 6 or 30 mg / kg S-baclofen. The effect of the treatment order was not statistically significant (p> 0.05).

Conclusion

The results of this experiment indicate that there is a dose dependent reduction in burial behavior of berlinds in racemic baclofen treated Fmr KO mice. When given separately, R-baclofen reduces the types of anxiety / obsessive / repetitive behavior evaluated in this trial. S-baclofen also altered berber burial behavior in a dose-dependent manner, however, at the dose of 1 mg / kg, Fmr KO mice actually buried more berlinds, suggesting that this dose may have an effect opposite desired effect. Fmr KO mice receiving a dose of 50 mg / kg, however, buried fewer beryls indicating that this high dose reduced the types of anxiety / obsessive / repetitive behavior evaluated in this trial. Together, these results suggest that R-baclofen may be more adequate than S-baclofen in reducing the types of anxiety / obsessive / repetitive behavior simulated by the berlinds test. AUDIOGENIC CONVULSATION ASSAY Experimental objective The aim of the experiment was to determine whether sensitivity to audiogenic seizures is reduced in Fmr KO mice following administration of the GABA-B receptor agonist B-baclofen and / or S-baclofen. In these experiments, Fmr KO mice received an intraperitoneal injection of R-baclofen or S-baclofen and were tested for audiogenic seizures.

Results

The results of the experiment demonstrate that R (+) - baclofen, but not S (-) - baclofen, reduces audiogenic seizures in Fmr KO mice. About 70-80% of vehicle treated Fmrl KO mice and S (-) - baclofen (3 mg / kg) exhibited an audiogenic convulsion. In contrast, only 33% of the R (+) - baclofen-treated Fmrl KO mice exhibited seizures.

Conclusions

The results demonstrate that R (+) - baclofen, but not S (-) - baclofen, reduces audiogenic seizures in Fmrl KO mice and that R-baclofen is more effective than S-baclofen in reducing this type of seizure environmentally induced in FmRl KO mice. Methods

The methods employed in the audiogenic seizure experiments are as previously described (Yan, QJ, et al., Genes Brain Behav 3: 337-359 (2004); Yan, QJ, et al., Neuropharm 49: 1053-1066 (2005)). Briefly, Fmrl knockout mice were treated intraperitoneally with vehicle, R-baclofen or S-baclofen about 60 minutes before the assay. Mice were exposed to high intensity sound and then observed for seizures. The primary end point was the frequency of status epilepticus, a sustained tonic seizure that very often results in respiratory arrest and death.

Test and control articles were administered to the mice one hour prior to training, via intraperitoneal (i.p.) injections, in a volume of 0.1 ml / 10 g body weight.

Mice were injected (i.p.) with a dose of R (+) - or S (-) - baclofen 45 minutes prior to the test. Each mouse was injected with a dose of R or S prior to the test. The mice used in this study were experimentally naive.

Two-three mice were placed in clean cages with strata and transferred from their holding cage to an attenuated sound chamber. The cage was placed under a cover that contained two Radio Shack Personal Alarms. After 1 min, the alarm sound was switched on for two minutes. After this two minute exposure, the mice were given another minute without sound followed by a second two minute alarm. The presence of seizures, as defined by the wild race not due to fright or tonic / clonic seizures, was recorded. In our test protocol, mice did not exhibit a seizure during the first alarm period. The following number (N) of mice was used for the study: 0 mg / kg N = 10; 3 mg / kg R (+) - baclofen N = 9; and 3 mg / kg S (-) - baclofen N = 9. The presence of seizures, as defined by wild-type race not due to tonic / clonic scares or convulsions, was recorded. The percentage of mice exhibiting seizures was analyzed using SPSS 11.0 software.

Results R-baclofen (3 mg / kg) significantly prevented the induction of audiogenic seizures, whereas S-baclofen, at the same dose, was no more effective than the vehicle (Figure 4). Figure 4 demonstrates that about 70% of the vehicle treated FmR1 KO mice exhibited audiogenic seizures. Similarly, about 78% of the Fmr KO mice treated with about 3 mg / kg of S (-) - baclofen exhibited convulsions. In contrast, only about 33% of the Fmrl KO mice treated with 3 mg / kg R (+) - baclofen showed seizures.

Conclusion

These results suggest that R-baclofen is probably more effective than S-baclofen in reducing this type of environmentally induced seizures in Fmrl KO mice.

OPEN FIELD TESTS

Experimental objective The aim of the experiment was to determine whether open field activity is altered in Fmr KO mice following administration of the GABA-B receptor agonist B-baclofen and / or S-baclofen. In these experiments, Fmr KO mice received an intraperitoneal injection of R-baclofen or S-baclofen and were tested for open field activity.

Results

The results of the experiment demonstrate that R (+) - baclofen and S (-) - baclofen reduce the open field activity of Fmr KO mice. Regarding vehicle-treated wild-type (WT) brood controls, vehicle-treated Fmr1 KO mice were significantly more active in the open field as measured by total activity. There was a significant dose-dependent reduction in exploratory activity as measured by total distance in FmR1 KO mice which received an intraperitoneal injection of R (+) - or S (-) - baclofen 1 hour before the test. Specifically, Fmr KO mice receiving a 6 mg / kg dose of R (+) - baclofen were less active (reduced total distance) compared to FmR1 KO mice that received the vehicle. Similarly, Fmrl KO mice receiving a 50 mg / kg dose of R (+) - baclofen were less active (reduced total distance) compared to Fmrl KO mice that received vehicle.

Conclusions

These data demonstrate that there was a dose-dependent reduction in exploratory activity in R (+) - or S (-) - baclofen treated Fmrl KO mice. Similar to individuals with fragile X syndrome, Fmr-deficient male mice were more active, but this increased activity, as measured by the total distance traveled in the open field arena, can be normalized with baclofen. The data suggest that the required dose of S-baclofen which reduces exploratory activity in Fmrl KO mice is greater than that required for R-baclofen-treated mice. Thus, R-baclofen may be more effective than S-baclofen in reducing the type of increased activity stimulated by the open field test. Methods

Test and control articles were administered to the mice one hour prior to training, via intraperitoneal (i.p.) injections, in a volume of 0.1 ml / 10 g body weight.

Mice were injected (i.p.) with a dose of R (+) - or S (-) - baclofen one hour prior to the test. Each mouse was injected with a dose of R or S prior to the test. The order of the treatment (e.g., R followed by S, or S followed by R) was equilibrated, and the dose was randomly assigned to each drug. There were at least 3 days between the tests. Mice used for this experiment had been previously tested approximately one week before in the burial test of berlinds after treatment with R (+) and S (-) - baclofen.

Mice were placed in the center of a clear Plexiglas open field arena (40 cm x 40 cm x 30 cm) allowing them to be harvested for 30 minutes. Bright aerial illumination provided approximately 800 lux of illumination within the sands. White noise was present in the arenas at about 55 dB. Data from the total distance walked during the 30-minute test were collected at two-minute intervals by a computer-operated animal activity optical system (Accuscan Eletronics), but data for the full 30-minute test were analyzed.

The following numbers (N) of mice were used for the various doses of R (+) - baclofen: N = 12.0 mg / kg; N = 13, 1.0 mg / kg; N = 13, 6.0 mg / kg. The following numbers (N) of mice were used for the various doses of S (-) - baclofen: N = 12.0 mg / kg; N = 14, 1.0 mg / kg; N = 12, 50.0 mg / kg. The N for the WT controls of the litter were: treatment with vehicle R (+) - baclofen N = 14; treatment with S (-) - baclofen N = 16 vehicle.

Data from the open field activity were analyzed using a two step process. First, the data from vehicle treated WT mice and Fmrl KO brood mice were analyzed using a one-way ANOVA. Next, the data for FmrI KO mice for the three doses of each compound were analyzed to determine whether the treatment significantly altered the behavior of the FmrI KO mice. Statistical analyzes were analyzed with SPSS 11.0 software.

Results R (+) - baclofen Figure 5 demonstrates that there was a significant (p <0.001) increase in locomotor activity in vehicle treated Fmrl KO mice compared to vehicle treated WT controls. In addition, there was a dose-dependent change in total distance walked on Fmr KO mice that received an intraperitoneal injection of R-baclofen 1 hour before the test. Fmr KO mice receiving a dose of 6 mg / kg were significantly less active (p = 0.018) than the vehicle treated FmR1 KO mice. S (-) - baclofen Figure 5 demonstrates that there was a significant (p <0.05) increase in locomotor activity in vehicle treated Fmrl KO mice compared to vehicle treated WT controls. In addition, there was a dose-dependent change in total distance walked on Fmr KO mice that received an intraperitoneal injection of S-baclofen 1 hour before the test. Specifically, Fmrl KO mice receiving a dose of 50 mg / kg were significantly less active (p = 0.021) than the vehicle treated Fmr1 KO mice.

Conclusions

These data demonstrate that there is a dose-dependent reduction in locomotor activity in R (+) - baclofen-treated Fmrl KO mice indicating that R (+) - baclofen reduces Fmrl KO hyperactivity as assessed in this assay. In addition, S-baclofen reduced Fmr1 KO activity in a dose-dependent manner. A lower dose of R (+) - baclofen was effective in reducing Fm 1 KO hyperactivity relative to S (-) - baclofen. R (+) - baclofen may be more suitable than S (-) - baclofen in reducing the type of hyperactivity in FmR1 KO mice stimulated by the open field test.

Pre-Clinical Summary R-baclofen was more than 10-fold more potent than S-baclofen as a GABA-B aqonist (Table 3) and also more potent for the inhibition of burial behavior of berlinds (Figures 2 and 3 ). Similarly, R-baclofen is more potent for the inhibition of audiogenic seizures than S-baclofen (Figure 4) and open field tests (Figure 5). EXAMPLE 7: TREATMENT OF FRAGILE MURGAS X WITH A MIXING MUSCLE RECEPTOR ANTAGONIST Diclclomine reduces berlind burial behavior in Fmrl knockout mice (Figure 6). Berber burial behavior is accepted as reflecting related anxiety, and obsessive / compulsive and persevering responses and, as such, mimics the symptoms commonly observed in subjects with fragile X syndrome and other disorders of brain development. Similarly, dicyclomine inhibited audiogenic seizures in Fmrl knockout mice (Figure 7). Increased susceptibility for audiogenic seizures in Fmrl knockout mice is accepted as modeling the increased prevalence of seizure disorders in FXS subjects.

BERLINDES ENTERTAINMENT TEST

Methods

Fmrl KO mice were raised on a C57BL / 6J gene pool. Only Fmrl KO (Fmrh7?) Male mice were tested in this study. A standard mouse cage was filled with 10 cm of stratum of corn cobs. Small (1.5-2 cm) black marbles were placed equidistantly at the top of the stratum. A mouse was placed in the cage allowing it to explore and burial the berlindes. After about 20 minutes, the mouse was removed and the number of buried berlinds (a berlinde considered to be buried if more than 50% of this was found underneath the stratum) were recorded. Mice were treated with dicyclomine about 60 minutes before the test.

Results

Fmr KO mice on this genetic background buried more berlinds than mice from the same wild-type (wt) litter. The administration of dicyclomine reduced berber burial behavior in a dose-dependent manner (Figure 6).

Conclusion

These data demonstrate that there is a dose dependent reduction in burial behavior of berlinds in dicloclomine treated Fmrl KO mice. Dicyclomine reduced the types of anxiety / obsessional / repetitive type behavior evaluated in this trial.

ASSAY OF AUDIOGENIC CONVULSIONS Methods

The methods employed are described above. Briefly, Fmrl knockout mice were treated i.p. with vehicle or dicyclomine for 60 minutes prior to the assay. Mice were exposed to high intensity sound and then observed for seizures. The primary end point was the frequency of status epilepticus, a sustained tonic seizure that very often results in respiratory arrest and death.

Results Dicyclomine significantly prevented the induction of audiogenic seizures (Figure 7).

Conclusion

These data demonstrate that dicyclomine efficiently rescues seizures in FmR1 KO mice.

EQUIVALENTS

Although this invention has been particularly illustrated and described with reference to preferred embodiments, it will be understood by those skilled in the art that various changes may be made to the shape and details thereof without departing from the scope of the invention falling within the scope of the appended claims.

SEQUENCE LISTING <110> SeaSide Therapeutics, LLC Roberts, Kathryn Carpenter, Randall L. <120> Methods of Treatment of Mental Retardation, Down Syndrome, Fragile X Syndrome <130> 3933.1008002 <150> US 60 / 860,733 < 151> 2006-11-22 <160> 3 <170> FastSEQ for Windows Version 4.0

<210> 1 <211> 24 <212> RNA <213> Artificial Sequence <220> <223> Primer <400> 1 gtggttagct aaagtgagga tgat 24

<210> 2 <211> 24 <212> RNA <213> Artificial Sequence <220> <223> Primer <400> 2 caggtttgtt gggattaaca gatc 24

<210> 3 <211> 19 <212> RNA <213> Artificial Sequence <220> <223> Primer <400> 3 tgggctctat ggcttctga 19

Claims (30)

A composition for use in the improvement of at least one member selected from the group consisting of a social domain and a communication domain in a human having autism, wherein the composition comprises a therapeutically effective amount of at least one gamma acid agonist aminobutyric acid. A composition for use in the improvement of at least one member selected from the group consisting of a social domain and a communication domain in a human having an autism spectrum disorder, wherein the composition comprises a therapeutically effective amount of at least one a gamma-aminobutyric acid agonist. A composition for use in the treatment of a human having fragile X syndrome, wherein the composition comprises a therapeutically effective amount of at least one gamma-aminobutyric acid agonist. A composition for use in the treatment of a human having Down syndrome, wherein the composition comprises a therapeutically effective amount of at least one gamma-aminobutyric acid agonist. A composition for use in the improvement of a social domain in a human having autism, wherein the composition comprises a therapeutically effective amount of at least one gamma-aminobutyric acid agonist. A composition for use according to any one of the preceding claims, wherein the gamma-aminobutyric acid agonist (GABA) includes a GABA agonist (B). A composition for use according to claim 3 or claim 6, wherein the GABA agonist (B) comprises baclofen, preferably R-baclofen. A composition for use according to claim 7, wherein the baclofen is at least about 80 mole percent of R-baclofen, at least about 85 mole percent of R-baclofen, at least about 90 per mole percent of R-baclofen, at least about 95 mole percent of R-baclofen or at least about 99 mole percent of R-baclofen. A composition for use according to any one of the preceding claims, further comprising administering to the human of at least one member selected from the group consisting of an antidepressant, an Î ± 2 -adrenergic agonist, an anticonvulsant, an agonist of a nicotinic receptor antagonist, an endocannabinoid receptor agonist, an anticonvulsant, an antipsychotic, an AMPA agonist, and a M1 muscarinic receptor antagonist. A composition for use according to claim 2 or claim 5, wherein the human further has fragile X syndrome. A composition for use according to any one of the preceding claims, further comprising administering at least one Group I mGluR antagonist to the human. A composition for use according to claim 11, wherein the Group I mGluR antagonist is an mGluR5 antagonist or an mGluR1 antagonist. A composition for use according to any one of the preceding claims, further comprising an improvement in the cognitive function of the human. A composition for use according to claim 13, wherein an improvement in cognitive function is an improvement in at least one member selected from the group consisting of memory, learning, attention, executive function, information processing, conceptualization , alert status, and troubleshooting. A composition for use according to claim 1 or claim 2, wherein the composition comprises a therapeutically effective amount of at least about 90 mole percent of R-baclofen relative to the total of R-baclofen and S -baclofen in the composition. A composition for use according to any one of the preceding claims wherein the improvement in the social domain in the human further comprises a decrease in at least one member selected from the group consisting of an obsessive compulsive disorder, a hyperexcitability disorder sensory, anxiety disorder, seizure disorder, irritability, aggression, startle tremors, repetitive / self-stimulatory behavior, ocular amusement, biting of hands, banging on the head and hitting others. A composition for use according to any one of the preceding claims wherein the improvement in the social domain includes an increase in at least one member selected from the group consisting of socialization, appropriate responses to spoken language, spontaneous attempts at interaction , eye contact, humor, motivation and calm. A composition for use according to any one of claims 1, 2 or 5 or the dependent claims thereof, further comprising an improvement in a communication domain in the human. A composition for use according to claim 18, wherein the improvement in a communication domain includes an improvement in verbal communication. A composition for use according to any one of the preceding claims, wherein the composition is for the reduction of at least one member selected from the group consisting of irritability and aggression in a human having autism. A composition for use according to any one of the preceding claims, wherein the gamma-aminobutyric acid agonist, the GABA agonist (B), the baclofen or the R-baclofen are administered orally to the human. A composition for use according to any one of the preceding claims, wherein the gamma-aminobutyric acid agonist, baclofen or R-baclofen is administered to the human in a dose of about 2.5 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, about 45 mg, about 50 mg or about 100 mg. The composition for use according to claim 22, wherein the gamma-aminobutyric acid agonist, baclofen or R-baclofen is administered in a single daily dose, or in two daily doses, or three daily doses, or four daily doses or five daily doses, or in multiple daily doses. A composition for use according to any one of the preceding claims, wherein at least one of a social domain, a communication domain and a cognitive domain are improved in the human upon treatment with the gamma-aminobutyric acid agonist. A composition for use according to any one of the preceding claims, wherein the social domain of the human is improved. A composition for use according to claim 24, wherein the communication domain is improved. A composition for use according to claim 24, wherein the cognitive function is improved. A composition for use in reducing at least one member selected from the group consisting of irritability and aggressiveness in a human having fragile X syndrome, wherein the composition comprises a therapeutically effective amount of at least one gamma- aminobutyric acid. A composition for use in the improvement of at least one member selected from the group consisting of a social domain and a communication domain in a human having fragile X syndrome, wherein the composition is an oral composition comprising a therapeutically effective amount of at least about 99 mole percent R-baclofen relative to the total R-baclofen and S-baclofen. A composition for use in the improvement of at least one member selected from the group consisting of irritability and aggressiveness in a human having fragile X syndrome, wherein the composition is an oral composition comprising a therapeutically effective amount of at least about of 99 mole percent R-baclofen relative to total R-baclofen and S-baclofen.